Aminophosphonates have attracted great attention among scientists including chemists, biochemists, and biologists due to their broad spectrum of biomedical applications. They are well known as pharmaceutically and biologically important compounds. Due to intensive studies on aminophosphonate derivatives in medicinal chemistry, various aminophosphonate derivatives including α-aminophosphonates, β-aminophosphonates, and γ-aminophosphonates have been synthesized over the past several decades (Palacios et al. (2005) Chemical Reviews 105(3): 899-932; Bhagat et al. (2007) The Journal of Organic Chemistry 72(4): 1263-1270; Ordonez et al. (2009) Tetrahedron 65(1): 17-49; Mucha et al. (2011) Journal of Medicinal Chemistry 54(17): 5955-5980; Naydenova et al. (2007) Amino Acids 33(4): 695-702; Lavielle et al. (1991) Journal of Medicinal Chemistry 34(7): 1998-2003).
α-N-heterocyclic phosphonic acids and their derivatives such as morpholine (Ghosh et al. (2004) J. Med. Chem. 47: 175-187; Yang et al. (2004) Bioorg. Med. Chem. Lett. 14: 3017-3025), piperazinyl (Yang et al. (2004) Bioorg. Med. Chem. Lett. 14: 3017-3025; Chaudhary et al. (2006) Bioorg. Med. Chem. 14: 1819-1826; Younes (1994) J. Pharm. Belg. 49: 119-125), or thiomorpholino-methyl phosphonates (Amar et al. (2008) Mater. Chem. Phys. 110: 1-6) are an important class of amino phosphonate compounds. They have received considerable interest from a number of areas, ranging from medicinal chemistry to materials sciences. Morpholino-methyl bisphosphonic acid has shown antimalarial activity (Ghosh et al. (2004) J. Med. Chem. 47: 175-187) and the morpholino-aryl-methyl phosphonate has been realized as an effective agonist of endothelial target for acetylcholine (ETA) (Yang et al. (2004) Bioorg. Med. Chem. Lett. 14: 3017-3025). Piperazinyl-methyl phosphonate derivatives have proven to be potent active pharmaceutical ingredients such as agonists of ETA (Yang et al. (2004) Bioorg. Med. Chem. Lett. 14: 3017-3025), antibacterial agents (Chaudhary et al. (2006) Bioorg. Med. Chem. 14: 1819-1826), calcium antagonists (Younes (1994) J. Pharm. Belg. 49: 119-125), and serotonin receptors (Lewkowski et al. (2015) Heteroat. Chem. 26: 290-298). These significant biological activities of α-amino phosphonates are associated with the structural analogues of the corresponding amino acids and mimics of the transition state of peptide hydrolysis (Kafarski and Lejczak (1991) Phosphorus, Sulfur Silicon Relat. Elem. 63: 193-215; Allen et al. (1978) Nature 272: 56-58). In addition, thiomorpholino-methyl phosphonic acid is known as an effective corrosion inhibitor for carbon steel in seawater (Amar et al. (2008) Mater. Chem. Phys. 110: 1-6).
Since the pioneering early work by Kabachnick and Fields in 1952 (Fields (1952) J. Am. Chem. Soc. 74: 1528-1531; Kabachnik and Medved (1952) Doklady Akademii Nauk SSSR 83: 689-692), the multicomponent reaction involving amine, aldehyde, and dialkyl phosphonate has emerged as a straightforward protocol towards α-aminophosphonic acid esters. This transformation proceeds via an in-situ imine formation, followed by phospha-Mannich reaction (Pudovik reaction) (Pudovik and Konovalova (1979) Synthesis 81-96) between phosphite nucleophile and imine electrophile, constructing an N-C-P motif. This method offers important advantages such as a simple one-pot process and a rapid increase of molecular complexity using readily available starting materials. Recently, with the surging interest in the application of α-N-heterocyclic phosphonate derivatives to medicinal and materials chemistry, a considerable emphasis has been placed on the reaction system that utilizes cyclic secondary amines. Phospha-Mannich reaction employing primary amine has been well exploited (Ordonez et al. (2009) Tetrahedron 65: 17-49; Azizi et al. (2014) Tet. Lett. 55: 7236-7239; Qian and Huang (1998) J. Org. Chem. 63: 4125-4128; Kasthuraiah et al. (2007) Heteroat. Chem. 18: 2-8), however, secondary amine involved reactions are scarcely developed. Dialkyl phosphonates stable towards hydrolysis and oxidation due to the lack of lone pair electrons have been extensively used for this phosphonylation to form a C—P bond (Stawinski and Kraszewski (2002) Acc. Chem. Res. 35: 952-960; Doak and Freedman (1961) Chem. Rev. 61: 31-44; Ma (2006) Chem. Soc. Rev. 35: 630-636; Kumar et al. (2014) Tetrahedron 70: 7044-7049; Suyama et al. (2010) Angew. Chem. Int. Ed. 49: 797-799; Sobhani et al. (2014) RSC Adv. 4: 15797-15806). They, however, are unreactive phosphorus species. On the other hand, trialkyl phosphites are highly reactive nucleophiles but they are susceptible to spontaneous aerobic oxidation to form inactive phosphates (Stawinski and Kraszewski (2002) Acc. Chem. Res. 35: 952-960; Doak and Freedman (1961) Chem. Rev. 61: 31-44; Ma (2006) Chem. Soc. Rev. 35: 630-636). Thus, strategies for generating highly nucleophilic phosphite species in-situ using dialkyl phosphonates for phospha-Mannich reaction have been developed over the past decades. The dialkyl phosphonates are activated by Lewis acids (Bhagat and Chakraborti (2007) J. Org. Chem. 72: 1263-1270) or magnetic nanoparticles (Reddy et al. (2015) New J. Chem. 39: 9605-9610; Ma'mani et al. (2009) Curr. Org. Chem. 13: 758-762; Reddy et al. (2011) Tetrahedron Lett. 52: 1359-1362; Nazish et al. (2014) Chem Plus Chem 79: 1753-1760; Sheykhan et al. (2011) J. Mol. Catal. A: Chem. 335: 253-261) to generate the nucleophilic dialkyl phosphites, which rapidly react with imminium intermediates to ultimately construct the α-N-heterocyclic phosphonates. Brønsted acid-catalyzed reaction with dialkyl phosphonates (Malamiri et al. (2014) J. Chem. Sci. 126: 807; Prauda et al. (2007) Synth. Commun. 37: 317-322; Zakharov et al. (2004) Russ. J. Gen. Chem. 74: 873-881) and Lewis acid-mediated transformation involving trialkyl phosphites (Makarov et al. (2015) Mendeleev Commun. 25: 232-233; Azizi and Saidi (2003) Tetrahedron 59: 5329-5332; Malhiac et al. (1996) Phosphorus, Sulfur Silicon Relat. Elem. 113: 299-301) are important alternative routes for the synthesis of tertiary α-aminophosphonates.
Despite the great efforts devoted to the synthesis of biologically significant α-N-heterocyclic phosphonates, there remain limitations such as the use of toxic metals, low product yields with especially secondary amines, and harsh reaction conditions (elevated temperatures and basic conditions). Consequently, the development of a general and direct method of phosphonylation for accessing various α-aminophosphonates under metal-free mild reaction conditions is highly desirable in synthetic organic chemistry. These needs and others are met by the present invention.